Compounds and methods for treating alcohol disorder

This application claims priority to U.S. Provisional Application No. 63/119,211, filed Nov. 30, 2020 and U.S. Provisional Application No. 63/202,424, filed Jun. 10, 2021, each of which is hereby incorporated by reference in its entirety.

Embodiments disclosed herein are directed, in part, to compounds, or pharmaceutically acceptable salts or solvates thereof, for modulating the activity of aldehyde dehydrogenase such as ALDH2 and/or methods for treating and/or preventing an alcohol related disorder such as, but not limited to, alcohol use disorder, alcohol induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal, and the like and/or methods for reducing the amount of alcohol consumed, reducing alcoholic cravings, or increasing the percentage of no heavy drinking days for a subject with alcohol use disorder.

Aldehyde dehydrogenase (ALDH) is a polymorphic enzyme converting aldehydes to carboxylic acids through oxidation. ALDH1 and ALDH2 are the most important enzymes for aldehyde oxidation, and both are tetrameric enzymes composed of 54 kDa subunits. Aldehyde dehydrogenase, mitochondrial (ALDH2) is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation.

Aldehyde dehydrogenase, mitochondrial (ALDH2) has long been of interest as a target for potential treatments for alcohol abuse. Recent evidence suggests that modulating the activity of ALDH2 such as ALDH2 inhibition, may be beneficial in the treatment of a variety of an alcohol related disorder, such alcohol use disorder, alcohol induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal, and the like. Thus, there is a need to identify an ALDH2 modulator for the treatment of these and other conditions. The present embodiments described herein fulfill these needs and others.

The disclosure is directed to compounds, or pharmaceutically acceptable salts or solvates thereof, or pharmaceutical compositions thereof, which, in part, modulate the activity of the ALDH2. The compounds can have, for example, a formula as described herein. In some embodiments, the compound is selected from a compound described herein. In some embodiments, methods of treating and/or preventing the conditions described herein are provided. In some embodiments, the condition is an alcohol related disorder such as, but not limited to, alcohol use disorder, alcohol induced disorder, alcohol abuse, alcohol dependence, alcohol intoxication, alcohol withdrawal, and the like.

In some embodiments, the compound has a formula of Formula (I), Formula (I-a), Formula (I-b), or Formula (III):

or a pharmaceutically acceptable salt or solvate thereof, wherein X, Y, R, R, and Rare as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.

In some embodiments, the compound has a formula of Formula (XIII), Formula (XIII-a), or Formula (XIII-b):

a pharmaceutically acceptable salt or solvate thereof, wherein X, Y, m, n, R, R, R, R, R, and Rare as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.

In some embodiments, the compound has a formula of Formula (IV), Formula (V), Formula (VI), or Formula (VII):

or a pharmaceutically acceptable salt or solvate thereof, wherein X, Y, Z, n, m, n′, m′, R, R, R, R, R, R, R, and Rare as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.

In some embodiments, the compound has a formula of Formula (VIII), Formula (IX), Formula (X), or Formula (XI):

or a pharmaceutically acceptable salt or solvate thereof, wherein X, U, j, j′, R, R, R, R, R, and Rare as provided for herein and, for example, can be selected from the respective groups of chemical moieties described herein. Also provided are processes for preparing these compounds.

In some embodiments, also provided are pharmaceutical compositions comprising one or more compounds as described herein, which can also comprise a pharmaceutically acceptable carrier. In some embodiments, the compounds described herein can be provided in any form, such as, but not limited to, a solid or solution (e.g., aqueous solution), as described herein. The compounds described herein, for example, can be obtained and employed in lyophilized form alone or with suitable additives.

Also provided are methods for treating and/or preventing alcohol related disorder in a subject or a subject in need thereof. In some embodiments, the alcohol related disorder is associated with aberrant ALDH2 activity as described herein. In some embodiments, the methods comprise administering one or more compounds or a pharmaceutical composition as described herein to a subject or a subject in need thereof.

In some embodiments, methods of reducing the amount of alcohol consumed in a subject with alcohol use disorder are provided. In some embodiments, the methods comprise administering one or more compounds or a pharmaceutical composition as described herein to a subject or a subject in need thereof.

In some embodiments, methods of reducing alcoholic cravings in a subject with alcohol use disorder are provided. In some embodiments, the methods comprise administering one or more compounds or a pharmaceutical composition as described herein to a subject or a subject in need thereof.

In some embodiments, methods of increasing the percentage of no heavy drinking days for a subject with alcohol use disorder are provided. In some embodiments, the methods comprise administering one or more compounds or a pharmaceutical composition as described herein to a subject or a subject in need thereof.

Stereoisomers of the compounds of the various formula provided herein, and pharmaceutical salts and solvates thereof, are also contemplated, described, and encompassed herein. Methods of using compounds of the formula provided herein are described, as well as pharmaceutical compositions including the compounds of the formula provided herein.

The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods that are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the embodiments include each and every individual subcombination of the members of such groups and ranges. For example, the term “Calkyl” or “C-Calkyl” is specifically intended to individually disclose methyl, ethyl, Calkyl, Calkyl, Calkyl, and Calkyl.

It is further appreciated that certain embodiments, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the embodiments, which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable sub-combination.

All percentages and ratios used herein, unless otherwise indicated, are by weight.

The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group, a spirocyclic group, or a fused or bridged bicyclic group, each of which has from 1 to 12 carbon atoms (“C-C”), or 1 to 6 carbons atoms (“C-C”), in the group. Examples of alkyl groups include methyl (Me, Calkyl), ethyl (Et, Calkyl), n-propyl (Calkyl), isopropyl (Calkyl), butyl (Calkyl), isobutyl (Calkyl), sec-butyl (Calkyl), tert-butyl (Calkyl), pentyl (Calkyl), isopentyl (Calkyl), tert-pentyl (Calkyl), hexyl (Calkyl), isohexyl (Calkyl), and the like. The term “spirocyclic group” refers to spirocyclic compounds in which the two rings share only one single atom, the spiro atom, which is usually a quaternary carbon. Examples of spirocyclic compounds are spiro[2,3]undecane, spiro[3,3]heptane, and spiro[5,5]undecane. The term “fused bicyclic group” refers to fused bicyclic compounds, in which two rings share two adjacent atoms. Examples of fused bicyclic compounds include bicyclo[4.4.0]decane, α-thujene and decalin, and the like. The term “bridged bicyclic group” refers to bridged bicyclic compounds, in which the two rings share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom. Examples of bridged bicyclic compounds include bicyclo[2.2.1]heptane, bicyclo[1,1,1]pentane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, bicyclo[3.3.3]undecane, and the like. The term “haloalkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C-C”), or 1 to 6 carbons atoms (“C-C”), in the group, wherein one or more of the hydrogen atoms in the group have been replaced by a halogen atom. Examples of haloalkyl groups include trifluoromethyl (—CF, Chaloalkyl), trifluoroethyl (—CHCF, Chaloalkyl), and the like.

The term “halo” or “halogen” refers to chloro, fluoro, bromo, or iodo.

The term “oxo” refers to an oxygen atom (i.e., ═O) as a divalent substituent, forming a carbonyl group when attached to a carbon (e.g. C═O), or attached to a nitrogen or sulfur heteroatom forming a nitroso, sulfinyl or sulfonyl.

The term “cycloalkyl” when used alone or as part of a substituent group refers to monocyclic, bicyclic, or tricyclic, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C-C”), or from 3 to 6 carbon atoms (“C-C”), or from 3 to 7 carbon atoms (“C-C”). Examples of cycloalkyl groups include, for example, cyclopropyl (C), cyclobutyl (C), cyclopropylmethyl (C), cyclopentyl (C), cyclohexyl (C), 1-methylcyclopropyl (C), 2-methylcyclopentyl (C), adamantanyl (C), and the like.

The term “heterocycloalkyl” when used alone or as part of a substituent group refers to any three to fourteen membered monocyclic, bicyclic, or tricyclic saturated ring structure containing at least one heteroatom selected from the group consisting of O, N, and S. Heterocycloalkyl groups may be described with respect to the number of atoms in the group, or with respect to the number of carbon atoms in the group. The term “bicyclic” ring structure refers to a spirocyclic, fused bicyclic, or bridged bicyclic ring. For example, the term “4-10 membered heterocycloalkyl” refers to a heterocycloalkyl group containing between 4 and 10 ring atoms. The term —C-Cheterocycloalkyl, for example, refers to a heterocycloalkyl group containing four to six carbon atoms. The heterocycloalkyl group may be attached at any heteroatom or carbon atom of the ring such that the result is a stable structure. Examples of suitable heterocycloalkyl groups include, but are not limited to, azepanyl, aziridinyl, azetidinyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, oxetanyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, Decahydroquinoline, 2-azaspiro[5.5]undecane, 6-oxa-3-azabicyclo[3.1.1]heptane, and the like.

The term “aryl” when used alone or as part of a substituent group refers to a mono- or bicyclic-aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring system. Examples of aryl groups are phenyl and naphthyl.

The term “heteroaryl” when used alone or as part of a substituent group refers to a mono-, bi-, or tricyclic-aromatic ring structure including carbon atoms as well as up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heteroaryl rings can include a total of 5, 6, 9, 10, or 14 ring atoms. Heteroaryl groups may be described with respect to the number of atoms in the group, or with respect to the number of carbon atoms in the group. Thus, the term “5-14 membered heteroaryl” refers to a heteroaryl group containing between 5 and 14 ring atoms. The term —C-Cheteroaryl, for example, refers to a heteroaryl group containing four to six carbon atoms. Examples of heteroaryl groups include but are not limited to, pyrrolyl, furyl, thiophenyl (thienyl), oxazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl, indolizinyl, indolyl, and the like.

When a range of carbon atoms is used herein, for example, C-Call ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C-C” includes C-C, C-C, C-C, C, C, and C. The range of carbon atoms may be expressed with alternative expressions. For example, the term “C” is an alternative expression of “C-C”.

When a ring system is described herein as having a range of members, for example, “5-14-membered”, all ranges, as well as individual numbers of atoms are encompassed. For example, “5-14-membered” includes 5-6-membered, 5-10-membered, 6-9-membered, 5-membered, 6-membered, 7-membered, 8-membered, and the like.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like.

The term “alkenyl” when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C-C”), or 2 to 6 carbons atoms (“C”), in the group, wherein the group includes at least one carbon-carbon double bond of alkenyl groups include vinyl (—CH═CH; Calkenyl), allyl (—CH— CH═CH; Calkenyl), propenyl (—CH═CHCH; Calkenyl); isopropenyl (—C(CH)═CH; Calkenyl), butenyl (—CH═CHCHCH; Calkenyl), sec-butenyl (—C(CH)═CHCH; Calkenyl), iso-butenyl (—CH═C(CH); Calkenyl), 2-butenyl (—CHCH═CHCH; Calkyl), pentenyl (CH═CHCHCHCHor CH═CHCHCHCH—; Calkenyl), and the like.

The term “alkynyl” when used alone or as part of a substituent group refers to a straight- or branched-chain group having from 2 to 12 carbon atoms (“C-C”), or 2 to 6 carbons atoms (“C-C”), in the group, wherein the group includes at least one carbon-carbon triple bond. Examples of alkynyl groups include ethynyl (—C≡CH; Calkynyl), propargyl (—CH— CH—CH; Calkynyl), and the like.

The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds provided herein that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present embodiments. Geometric isomers of the compounds of the present embodiments are described and may be isolated as a mixture of isomers or as separated isomeric forms.

Compounds provided herein may also include tautomeric forms. All tautomeric forms are encompassed.

In some embodiments, the compounds may exist as rotational isomers. In some embodiments, the compounds exist as mixtures of rotational isomers in any proportion. In other embodiments, the compounds exist as particular rotational isomers, substantially free of other rotational isomers.

Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

In some embodiments, the compounds, and salts thereof, are substantially isolated. By “substantially isolated” is meant that the compound is at least partially or substantially separated from the environment in which is formed or detected. Partial separation can include, for example, a composition enriched in the compound. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

Also provided herein are pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as, but not limited to, amines; alkali or organic salts of acidic residues such as, but not limited to, carboxylic acids; and the like. The pharmaceutically acceptable salts include, but are not limited to, the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts can be synthesized from the parent compound, which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are can be used. Lists of suitable salts are found in17ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and66, 2 (1977), each of which is incorporated herein by reference in its entirety.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

A “pharmaceutically acceptable excipient” refers to a substance that is non-toxic, biologically tolerable, and otherwise biologically suitable for administration to a subject, such as an inert substance, added to a pharmacological composition or otherwise used as a vehicle, carrier, or diluent to facilitate administration of an agent and that is compatible therewith. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

A “solvate” refers to a physical association of a compound provided herein with one or more solvent molecules.

“Subject” includes humans. The terms “human,” “patient,” and “subject” are used interchangeably herein.

As used herein, the phrase “in need thereof” means that the animal or mammal (subject) has been identified as having a need for the particular method or treatment. In some embodiments, the identification can be by any means of diagnosis. In any of the methods and treatments described herein, the animal or mammal can be in need thereof. In some embodiments, the animal or mammal is in an environment or will be traveling to an environment in which a particular disease, disorder, or condition is prevalent. In some embodiments, the subject in need thereof is suspected of having the condition that needs to be treated.

“Treating” or “treatment” of any disease or disorder refers, in some embodiments, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment, “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder. In some embodiments, the disease or disorder is alcohol related disorder.

As used herein, the phrase “integer from X to Y” means any integer that includes the endpoints. For example, the phrase “integer from X to Y” or “1-5” or “1 to 5” means 1, 2, 3, 4, or 5 or any value therein if not modified by the term “integer.”

Additionally, unless defined otherwise, all technical and scientific terms have the same meaning as is commonly understood by one of ordinary skill in the art to which the embodiments disclosed belongs.

As used herein, the terms “a” or “an” means that “at least one” or “one or more” unless the context clearly indicates otherwise.